Upregulation of Angiotensin II Type 2 Receptor and Limitation of Myocardial Stunning by Angiotensin II Type 1 Receptor Blockers during Reperfused Myocardial Infarction in the Rat

BACKGROUND: We have previously shown that angiotensin II type 1 receptor blockers induce cardioprotection and upregulate angiotensin II type 2 receptor during in vivo postischemic-reperfusion in dogs. Whether angiotensin II type 1 receptor blockers upregulate angiotensin II type 2 receptors in rats is controversial, and whether surmountable and insurmountable angiotensin II type 1 receptor blockers exert similar protective effects during reperfused myocardial infarction is not known. METHODS: We assessed the effects of the surmountable angiotensin receptor blocker valsartan, and the insurmountable angiotensin receptor blocker irbesartan, on hemodynamics and left ventricular systolic and diastolic function (echocardiography/Doppler) in vivo and infarct size (triphenyl tetrazolium chloride method), and regional angiotensin II type 1 receptor and angiotensin II type 2 receptor expression (immunoblots) ex vivo, after anterior reperfused myocardial infarction in rats. The rats were randomized to four groups: intravenous valsartan (10 mg/kg, n = 8), irbesartan (10 mg/kg, n = 8), or saline vehicle (controls, n = 14) over 30 minutes before reperfused myocardial infarction, and sham (n = 8). Angiotensin II type 1 receptor blockade was assessed by the inhibition of angiotensin II pressor responses. RESULTS: Compared with the control group, both angiotensin receptor blockers significantly decreased infarct size, limited the increase in left atrial pressure, improved positive left ventricular dP/dtmax and dP/dtmin, improved left ventricular ejection fraction and diastolic function, and limited infarct expansion after reperfused myocardial infarction. Both angiotensin receptor blockers increased angiotensin II type 2 receptor protein in the postischemic-reperfused zone, with no change in angiotensin II type 1 receptor protein. There were no changes in the sham group. CONCLUSION: The overall results indicate that the angiotensin receptor blockers valsartan and irbesartan both induce cardioprotection, limit myocardial stunning, and upregulate angiotensin II type 2 receptor protein expression after reperfused myocardial infarction in the rat. Patients who are already receiving angiotensin receptor blockers and develop acute coronary syndromes might benefit from these cardioprotective effects during reperfusion therapy.